Role of urothelial cells in BCG immunotherapy for superficial bladder cancer.

Intravesical instillation of Bacillus Calmette-Guérin (BCG) is used for the treatment of superficial bladder cancer, both to reduce the recurrence rate of bladder tumour and to diminish the risk of progression. Since its first therapeutic application in 1976, major research efforts have been directed to decipher the exact mechanism of action of the BCG-associated antitumour effect. Bacillus Calmette-Guérin causes an extensive local inflammatory reaction in the bladder wall. Of this, the massive appearance of cytokines in the urine of BCG-treated patients stands out. Activated lymphocytes and macrophages are the most likely sources of these cytokines, but at present other cellular sources such as urothelial tumour cells cannot be ruled out. Bacillus Calmette-Guérin is internalised and processed both by professional antigen-presenting cells and urothelial tumour cells, resulting in an altered gene expression of these cells that accumulates in the presentation of BCG antigens and secretion of particular cytokines.

A prospective longitudinal study comparing the impact of external radiation therapy with radical prostatectomy on health related quality of life (HRQOL) in prostate cancer patients.

BACKGROUND: The objective of the present study is to compare the impact on the general and disease-specific health related quality of life (HRQOL) of external radiation therapy (ERT) with radical prostatectomy (RP) in patients with localized prostate cancer, and to explore which factors, and to what extent, contribute to the assessed changes in HRQOL. METHODS: One hundred and thirty eight patients participated in this prospective longitudinal study. They completed before treatment (T0) and after 12 months (T1) a questionnaire constructed of validated instruments, measuring HRQOL and several psychosocial factors (PF). Among other things, multiple regression analyses including all baseline characteristics, HRQOL and PF were executed in order to meet the objectives. RESULTS: RP patients showed significantly more improvement in their emotional function, while they reported more incontinence and a worse sexual function. There was significantly more improvement in the overall HRQOL of ERT patients, while the changes in the gastrointestinal function of these patients were significantly worse. Only the differences with respect to incontinence can be attributed to the treatment itself. Almost all HRQOL change scores are primarily influenced by their own baseline score. The influence of other factors, like age, socioeconomic status, and several PF, is limited. CONCLUSIONS: The impact on HRQOL of ERT is similar to that of RP, except for incontinence. RP patients suffer more from incontinence than ERT patients. Changes in the assessed HRQOL are mainly influenced by the pre-treatment HRQOL scores.

Health-related quality of life and psychosocial factors in patients with prostate cancer scheduled for radical prostatectomy or external radiation therapy.

OBJECTIVE: To assess whether baseline health-related quality of life (HRQOL) and psychosocial profiles differ in patients with prostate cancer scheduled for radical prostatectomy (RP) or external radiation therapy (ERT), as there is evidence that HRQOL is influenced by psychosocial factors (PFs), so that any variation at baseline should be considered when comparing the effect of therapy on HRQOL. PATIENTS AND METHODS: Before receiving therapy, HRQOL and PFs were assessed in 65 patients scheduled for RP and in 73 scheduled for ERT. To measure HRQOL (generic and disease-specific) and PFs, an extended questionnaire was constructed, using validated and standardized instruments. Clinical data were collected from patients' medical records. Comparisons adjusted for age and socio-economic status (SES) were analysed using Student's t-test and univariate analyses of variance and covariance. RESULTS: Patients scheduled for ERT were 7.9 years older and had a lower SES (both P < 0.001), more often had stage T3 and T4 disease, had poorer histopathological differentiation and higher levels of prostate-specific antigen (all P < 0.01). They also reported a worse physical, role, cognitive and social function, more fatigue, more pain, a lower overall HRQOL and worse sexual function than patients scheduled for RP. There were no differences in urinary and bowel function, nor in the PFs assessed. CONCLUSION: The baseline HRQOL profile of patients scheduled for RP is better than in those scheduled for ERT. These results are in line with those from the few other studies on this subject. Knowing the impact of RP and ERT on HRQOL should therefore be based mainly on longitudinal studies including baseline measures, the analyses of which should be adjusted for age and SES. In the present small study, baseline PFs did not differ between the treatments.

The impact of androgen deprivation therapy on health related quality of life in asymptomatic men with lymph node positive prostate cancer.

PURPOSE: To evaluate the impact of androgen deprivation on health related quality of life (HRQOL) in patients with asymptomatic lymph node positive prostatic carcinoma (LPPC). MATERIALS AND METHODS: HRQOL domains were measured, using standard instruments in 91 patients with histologically proven LPPC. Most patients were randomized for immediate or deferred hormonal treatment until progression was observed. For analyses concerning the time to progression and survival the Kaplan-Meier method was used. RESULTS: Patients treated with androgen deprivation showed a significantly worse sexual, emotional, and physical function, experienced more hot flushes and a worse overall HRQOL, compared with patients receiving no therapy. Time to progression was significantly shorter in the deferred treated patients in comparison with the immediately treated patients (33 vs. 62 months, p<0.001). No significant differences were found with respect to the duration of survival. CONCLUSION: Hormonally treated patients with asymptomatic LPPC have a worse HRQOL compared with patients receiving no therapy. The duration of survival was similar, whether patients received immediate or deferred hormonal treatment. Nowadays, with patients' preferences playing an increasingly important role in therapeutic decision making, physicians should be aware of this negative impact and ought to inform the patients on this.

[The future of urology in Europe: a perspective from the European Urology Association]. / El futuro de la urología en Europa: una perspectiva desde la Asociación Europea de Urología.

INTRODUCTION: In order to be able to influence and monitor future developments for urologists, strategies should be promoted in advance to guarantee the future of the speciality and to accommodate the inevitable changes. Faced with this challenge, the EAU, through its Strategy Planning Office (SPO), has prepared a document which is offered, here, in abbreviated form, to the European and international urological communities for general consideration. MATERIAL AND METHODS: A group of subjects, related to the domains and internal consistency of urology as a speciality, were selected and discussed among the members of the SPO and later submitted to open consultation among distinguished members of the urological community. The topics selected for discussion included: what is urology; urology in the university; sub-specialization in urology; training in urology; does kidney transplantation belong to urology, and others. RESULTS: It is shown that urology is going through an exciting and hazardous transition period. Urology has conflicting problems in its traditional domains due to changes in health care policy, and internal identification problems due to its permanent expansion and sub-specialization options. Weaker points are its relation with primary care medicine (shared care options), the presence and role of urology in institutions such as the university, department of surgery, children's hospitals, administration, etc.; the desegregating effect of the sub-specialities; the increasing encroachment of other specialities, and the increasing outpatient effect of technological progress. CONCLUSIONS: An action plan is proposed to confront these changes without losing manpower, internal consistency or social image and improving patient care quality, excellence of training and scientific progress.

The future of urology in Europe: an overview from the European association of urology.

INTRODUCTION: In order to be able to influence and monitor future developments for urologists, strategies should be promoted in advance to guarantee the future of the speciality and to accommodate the inevitable changes. Faced with this challenge, the EAU, through its Strategy Planning Office (SPO), has prepared a document which is offered, here, in abbreviated form, to the European and international urological communities for general consideration. MATERIAL AND METHODS: A group of subjects, related to the domains and internal consistency of urology as a speciality, were selected and discussed among the members of the SPO and later submitted to open consultation among distinguished members of the urological community. The topics selected for discussion included: what is urology; urology in the university; sub-specialization in urology; training in urology; does kidney transplantation belong to urology, and others. RESULTS: It is shown that urology is going through an exciting and hazardous transition period. Urology has conflicting problems in its traditional domains due to changes in health care policy, and internal identification problems due to its permanent expansion and sub-specialization options. Weaker points are its relation with primary care medicine (shared care options), the presence and role of urology in institutions such as the university, department of surgery, children's hospitals, administration, etc.; the desegregating effect of the sub-specialities; the increasing encroachment of other specialities, and the increasing outpatient effect of technological progress. CONCLUSION: An action plan is proposed to confront these changes without loosing manpower, internal consistency or social image and improving patient care quality, excellence of training and scientific progress.

Transrectal ultrasonography in male subfertility patients: an intra- and interobserver study.

The purpose of this paper was to examine whether ultrasound abnormalities of the prostate and seminal vesicles, which may be related to male accessory gland infection, are reproducible. Forty-seven men attending an infertility clinic were studied. Imaging findings of transrectal ultrasonography were recorded. Kappa (kappa)-values to determine the intra- and inter-observer variation were assessed. Calcifications have good intra-observer (kappa = 0.77; 95% CI: 0.59-0.96) and good inter-observer reproducibility (kappa = 0.73; 95% CI: 0.54-0.93). Dilatation of the peri-prostatic plexus had moderate intra-observer (kappa = 0.57; 95% CI: 0.33-0.80) and good inter-observer reproducibility (kappa = 0.74; 95% CI: 0.55-0.94). Other ultrasound abnormalities of the prostate were not reproducible. None of the ultrasound abnormalities of the seminal vesicles were reproducible. In our study the prevalence of ultrasound abnormalities which may be related to male accessory gland infection was as high as 96%. However, only calcifications and dilatation of the venous plexus had good reproducibility. Other observed ultrasound abnormalities of the prostate and seminal vesicles were poorly reproducible and are therefore of no use in the diagnosis of male accessory gland infection.

Immunostimulation in the urinary bladder by local application of Nocardia rubra cell-wall skeletons (Rubratin) and bacillus Calmette-Guérin as therapy for superficial bladder cancer: a comparative study.

Twelve patients with superficial bladder cancer were treated with intravesical instillations of Rubratin (ASTA Pharma AG, Frankfurt, Germany), a cell-wall preparation of Nocardia rubra. The objective was to compare the immunostimulating effect of Rubratin with that of bacillus Calmette-Guérin (BCG). Local immunostimulation was determined by cytokine induction in serially collected urine samples during the first 24 h after each instillation, leukocyte influx into the urine, and phenotypic analysis of the lymphocyte fraction. Levels of Rubratin-induced interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha were significantly elevated compared with pretherapy levels. Rubratin induced leukocyte influx into the urine. T-cell activation (IL-2 receptor and human leukocyte antigen-DR expression) can be induced, and CD4:CD8 cell ratios can be increased. All parameters indicated that Rubratin-induced immunostimulation was less than that associated with BCG. In conclusion, although local Rubratin-induced immunostimulation occurs in a limited number of patients, the amount of immunocompetent cells attracted to the bladder seems to be less than that associated with BCG therapy, thus resulting in lower levels of cytokine production (which may reflect less clinical efficacy).

Quality of life assessment in patients with hormone-resistant prostate cancer treated with epirubicin or with epirubicin plus medroxy progesterone acetate - is it feasible?

OBJECTIVES: The optimal palliative treatment in patients with advanced hormone-resistant prostate cancer (AHRPC) is still under investigation. We studied the effect of epirubicin, alone or combined with medroxy progesterone acetate (MPA), in this particular patient group. The aim of the study was to investigate the feasibility of quality of life (QOL) measurement and to ascertain whether MPA added to epirubicin produces a better QOL than epirubicin alone. METHODS: Of 28 randomized patients with symptomatic AHRPC, 26 were eligible for the study. Fourteen of them received epirubicin (100 mg/m(2) i.v.) every 3 weeks in combination with an oral dose of 500 mg of MPA twice daily. Twelve patients received epirubicin alone. For the QOL assessment, the Rotterdam Symptom Checkliste was used. Toxic side effects of chemotherapy were assed by the WHO criteria. Subjective responses included performance status and pain score. RESULTS: Compliance in completing QOL questionnaires was high (87.5%). In none of the QOL domains studied did any of the patients, irrespective of their treatment, experience an improvement in their QOL. Moreover, after 12 and 24 weeks, patients in both treatment arms experienced a significant worsening of physical symptom distress when compared to study entry. Toxicity was moderate to severe. A biochemical response (drop in prostate-specific antigen of more than 50%) was observed in 5 out of 26 patients (19.1%) and a subjective response in 7 out of 26 patients (26.9%). The median survival for all patients was 30 weeks. There was no statistically significant difference between the two arms. Performance status and the global QOL as judged by the patients themselves were associated with the duration of survival. No relation was found between the initial observed subjective response and survival. CONCLUSIONS: The feasibility of measuring QOL in patients with symptomatic AHRPC is demonstrated in the present study. Subjective and biochemical responses were observed in both treatment arms, but these were not translatable as improved measured QOL domains.

Treatment of superficial bladder tumors: achievements and needs. The EORTC Genitourinary Group.

OBJECTIVE: The therapeutic objectives in the initial treatment of superficial tumors are to remove completely the tumor, to assess the need for further therapy and to plan the follow-up. METHODS/RESULTS: The EORTC Genitourinary Group assessed the percentage of patients with recurrence at 3 months (3RR) after complete resection of all visible lesions taking into account the institution, the number of tumors at presentation and the year of treatment. The 3RR was considered for 18 institutions. For single tumors, the 3RR varied from 0 to 36% and for multiple tumors from 7 to 75%. The 3RR by number of tumors was 8.7% for single tumors, 21% for 2-5 tumors and 32.2% for >5 tumors. The 3RR by year of entry for single tumors ranged from 21.0 to 43.8% during 1975-1978, from 6.3 to 12.7% during 1984-1986 and from 3 to 5.3% during 1987-1989. For multiple tumors it ranged from 50.0 to 61.5% during 1975-1978, from 20.2 to 27.3% during 1979-1983 and from 14.4 to 24.6% during 1984- 1986. The use of more refined instruments probably led to the decreasing percentage of the 3RR in more recent years, the large variation between institutions remains unexplained. The bladder's unique location renders its mucosa accessible to instillation of chemotherapeutic and immunotherapeutic agents. Cytostatics can be instilled into the bladder hours after surgery without severe complications. A single early instillation within 6 h after transurethral resection (TUR) in patients with a solitary bladder tumor category T(a)/T(1)G(1) to G(3) could reduce the recurrence rate per year by nearly 50%. The superiority of any of the commonly used intravesical drugs has never been demonstrated; the time to initiate therapy is important for treatment outcome. Optimal results can be achieved by initiating treatment early (within 24 h after TUR) and for a duration of 6 months, and maintenance (>6 months) for patients with a delayed first instillation (>7 days after TUR). Bacillus Calmette-Guérin (BCG) immunotherapy has been confirmed to be highly effective in the reduction of tumor recurrence, the treatment of residual papillary transitional cell carcinoma and the treatment of carcinoma in situ (CIS). The response rate in the treatment of the papillary disease averages 55%, and for CIS 73%. In the prevention of tumor recurrence the relative benefit of BCG is 45%. A direct prospective randomized comparison of BCG with intravesical chemotherapy has found it to be significantly superior to thiotepa, to doxorubicin and to mitomycin C when only patients with intermediate and high risk for recurrence were treated. In studies including patients with low recurrence risk, no advantage for BCG was found. Clinical trials showed no superiority of BCG immunotherapy to chemotherapy in preventing progression to > or =T(2). CONCLUSIONS: Investigation of the concept of chemoimmunotherapy up to now lacked evidence of advantages for this approach. Preventive regulatory measures directed to decrease tobacco smoking and some occupational exposures to aromatic amines may contribute to the reduction of bladder cancer. Bladder cancer is a multistep process making this tumor a candidate for chemoprevention. To date, retinoids are the best-studied chemopreventive agents achieving mixed clinical results in superficial bladder tumors. The potent apoptosis-inducing retinoid fenretinide is currently in the phase III trials. The follow-up of patients with all types of superficial tumors must be lifelong; unfortunately cystoscopy cannot be replaced yet by the control of any markers present or not in the urine. There is hope this may change in the near future.

Polymerase chain reaction based method for the detection of BCG retention after intravesical instillation in guinea pig bladders.

OBJECTIVE: In intravesical Bacille bilié de Calmette-Guérin (BCG) immunotherapy of superficial bladder cancer, a T cell mediated immunological reaction is associated with the antitumor activity. To gain insight into the approximate number of BCG bacteria retained in the normal, noninjured, urinary bladder after intravesical application responsible for induction of the immune reaction, the utility of a sensitive polymerase chain reaction (PCR) based assay was investigated in a guinea pig model. METHODS: After one single or six subsequent weekly instillations with 1x10(7) CFU of BCG, the bladders were resected and processed for BCG determination with PCR. The bladders were resected 24 h after instillation, aiming at (semi)quantifying the number of BCG organisms able to resist the natural voiding washout of the bladder. The PCR was based on amplification of a 249 base pair fragment of the insertion element IS6110 and is specific for bacteria belonging to the Mycobacterium tuberculosis complex which includes Mycobacterium bovis BCG. RESULTS: After one single instillation no detectable BCG retention was found. However, after six weekly instillations, BCG bacteria could be demonstrated in 2 out of 5 guinea pig bladders, indicating that the number of adhering BCG organisms was around the detection limit of the assay (600-1,000 BCG bacteria per bladder). CONCLUSIONS: The data suggest that after six instillations, the retention of BCG in the guinea pig bladder is enhanced as compared with one single instillation. This finding is suggestive of a role of the inflammatory process that is, besides immune system mediated reactions, associated with intravesical BCG instillations. The nature of the molecules involved in enhanced BCG retention after repeated instillations remains to be investigated.

An in vivo endoluminal ultrasonographic study of peristaltic activity in the distal porcine ureter.

PURPOSE: Experiments were performed to quantify the duration and frequency of ureteric peristaltic activity in the laparotomized and non-laparotomized pig in its virgin and postinstrumented states. MATERIALS AND METHODS: Pigs (n = 10) in a steady state of hydration were studied under halothane anesthesia in two groups. The study was undertaken in two separate sessions at a week's interval. In group I laparotomy and vesicotomy were undertaken to obtain ELUS images. In group II, peristalsis was studied using an ELUS probe introduced through the working channel of a 22F rigid cystoscope. Peristalsis was visualized as a periodic diameter-change of ureter and recorded (for approx. 30 minutes) on videotape after an initial period of adaptation of approx. 30 minutes. RESULTS: The ureter acts like a pump discharging urine into the bladder through peristaltic activity. ELUS imaging of ureteric peristalsis correlated well with "eyeballing" of the passage of peristalsis through a ureter (group I). The shortest peristaltic activity in group I was 6.0+/-2.0 seconds in the non-instrumented- and 5.1+/-1.4 seconds in the instrumented ureter. In group II it was 6.8+/-1.5 seconds in the non-instrumented- and 6.4+/-1.5 seconds in the instrumented ureter. Chronic dilatation of ureter led to decrease in peristalsis frequency. Interestingly, acute dilatation caused an increase in ureteric peristalsis frequency. CONCLUSIONS: Ureteric peristalsis acts as a pump discharging urinary boluses (intraluminal fluid load) unidirectionally into the bladder. ELUS provides us an opportunity to quantify and study ureteric peristalsis.

An electro-myographic study of the distal porcine ureter.

PURPOSE: The accumulation of urine in the renal pelvis causes depolarisation of non-specific muscular pace-maker cells. The wave of depolarisation spreads distally in the ureteric smooth muscle cells via gap junctions. This wave of excitation causes a coordinated peristaltic contraction which transports the urine bolus distally to the bladder. The EMG activity in the distal porcine ureter was studied and analyzed to establish the characteristics of ureteric excitation. MATERIALS AND METHODS: Ten female New Yorkshire pigs (50 to 60 kg.) were studied in two groups under light halothane anesthesia (5% at induction and 1% for maintenance anesthesia). In both groups each pig was studied in two separate sessions at a week's interval. In group I (n = 5), bipolar needle electrodes (o: 0. 09 mm.) were implanted through a lower mid-line abdominal incision in the posterior bladder wall, the trigone and the pelvic ureter at intervals of 3 and 8 cm., respectively, from the ureteric orifice. In group II (n = 5), EMG spike burst activity was studied using a twin bipolar ring-electrode attached to an endoluminal ureteric catheter. EMG complexes were recorded using 0 to 30 Hz filters. The duration of spike burst complexes and their intervals were analyzed using a Nicollet, Pathfinder II(R) machine and a Poly(R) 4.9 digital signal processing program. RESULTS: Two types of spike burst activity could be distinguished between the electrodes: A, the migrating type and B, the non-migrating type. Frequency distribution analysis of spike burst duration revealed two main classes in experimental group II, a short spike burst (96%) which lasted 4.5 +/- 1.8 seconds and a longer one lasting 13.4 +/- 1.5 seconds. The conduction velocity of the migrating spike bursts (n = 177, 42% of total) between the proximal and the distal electrode had an average of 2.3 +/- 1.3 cm./sec. No relationship was found between the duration of the proximal spike burst and the conduction velocity. Data from experimental group I correlated well with data from group II. CONCLUSIONS: The results of our EMG study in the distal ureter reveal an approximately 9 cm. long electrically active zone in >/= 90% of EMG activity recordings. The duration of activity was approximately 5 seconds. Such an excited segment of ureter led to a contraction which occluded the ureter and could prevent retrograde leakage of intraluminal contents.

Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee.

OBJECTIVES: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with Ta,T1 bladder cancer showed malignant disease: carcinoma in situ, or papillary tumor. We also investigated biopsies underlying the papillary tumor, adjacent to the tumor, and from suspicious-appearing mucosa. METHODS: In EORTC protocol 30863 (low-risk tumors), 393 patients underwent a biopsy of normal-appearing urothelium. In protocol 30911 (intermediate- and high-risk tumors), multiple biopsies were taken from normal- appearing urothelium in 602 patients. RESULTS: No abnormalities were found in the random biopsies of 376 (95.6%) patients with low-risk tumors and in 532 (88.4%) patients with intermediate- and high-risk tumors. Six (1.5%) patients with low-risk tumors and at least 21 (3.5%) patients with higher-risk tumors showed carcinoma in situ in their random biopsies. None of the patients in the low-risk group and 1 (0.2%) patient in higher-risk group had an invasive tumor (T2). CONCLUSIONS: This analysis indicates that biopsies of normal-appearing urothelium in Ta,T1 bladder cancer patients show no abnormalities in about 90% of the patients. Performing such biopsies does not contribute to the staging or to the choice of adjuvant therapy after transurethral resection.

A study of ureteric peristalsis using a single catheter to record EMG, impedance, and pressure changes.

Ureteric peristalsis transports a urinary bolus from the renal pelvis to the bladder. We developed an intraluminal catheter with a pressure transducer on it to study intraluminal pressure changes and a twin bipolar electrode to record the ureteric EMG and impedance (Z) changes during a peristaltic wave. Five female New Yorkshire pigs (50-60 kg) were studied under light halothane anesthesia (5% at induction/1% for maintenance). A steady state of hydration was maintained using intravenous saline infusion. EMG spike burst activity was studied at a 10-cm interval using low (0-30) Hz filters. Impedance between the same electrodes is measured simultaneously in higher frequencies (1-5 KHz) as a function of ureteric motor activity. Pressure generation in the ureteric lumen was also measured simultaneously by a transducer on the same catheter. A digital signal processing program (Poly 4.9) was used for analysis. Parenteral furosemide was used to induce diuresis. Resting ureteric impedance (Z(R)) decreases to Z(B) (Z bolus) during the passage of the urinary bolus. Passage of a contractile zone during a peristaltic wave increases impedance from Z(B) to its Z(R) level and initiates a pressure rise. Bolus length (the length Z(B)) is not constant and decreases distally. EMG corresponds well in time to impedance. Z(R) disappears after infusion of furosemide because of increased urine load and changes of intraluminal ionic environment. The contractile segment of a ureteric peristaltic wave appears to be represented by an elevated Z segment (Z(C)). Pressure rise is recorded only at the beginning of a contractile zone. A specially adapted intraluminal catheter can be used to study peristalsis in the upper urinary tract. One can study all the three components of ureteric peristalsis (excitation, contraction, and intraluminal pressure rise) using such a catheter.

Anatomy of ureterovesical junction and distal ureter studied by endoluminal ultrasonography in vitro.

PURPOSE: The emerging technique of endoluminal ultrasonography (ELUS) provides a new modality for endoscopic visualization of the urinary tract which needs to be further evaluated. We studied the normal anatomy of distal ureter and ureterovesical junction using ELUS. MATERIALS AND METHODS: An assessment of in vitro ELUS ureteric images undertaken at 1 mm. intervals from 8 fresh human cadaver pelvis blocs of bladder and distal ureter were compared with findings of serial histological sections of the same specimens (stained for cholinesterase isoenzymes) to assess the degree of correlation. Computer-assisted 3D reconstructions were made. RESULTS: The different components (ureteric, detrusor and periureteric tissue) of the UVJ could be identified on the basis of echogenicity and form, but differentiation between the respective muscle layers in the wall of the ureter or of the detrusor was not possible. Nevertheless, ureteric volume measurements and an assessment of transmural ureteric length and the angle of passage through the bladder wall were possible. CONCLUSIONS: ELUS is able to differentiate between the ureteric and detrusor muscle and the UVJ gross anatomy can be reconstructed. ELUS technology, however, fails to differentiate between individual muscular layers of the ureter or the detrusor. Further improvement in ELUS is mandatory.

Urinary interleukin-2 monitoring during prolonged bacillus Calmette-Guerin treatment: can it predict the optimal number of instillations?

PURPOSE: In patients with superficial bladder cancer treated with a first 6-week instillation course of bacillus Calmette-Guerin (BCG) the induction pattern of urinary interleukin (IL)-2 has been described, and the levels of urinary IL-2 were associated with the clinical response to BCG treatment. We evaluated urinary IL-2 kinetics in patients with recurrent superficial bladder tumor receiving a second or third 6-week BCG instillation course. To our knowledge there have been no studies of prolonged BCG treatment and urinary cytokine responses. MATERIALS AND METHODS: Urinary IL-2 was determined in 12 patients with superficial transitional cell carcinoma of the bladder receiving a complete (6-week) second or third BCG instillation course and in 3 patients receiving 3 BCG instillations during a maintenance schedule at month 3. Urinary IL-2 was determined with an enzyme-linked immunosorbent assay using an oligoclonal system. RESULTS: Of 12 patients 10 had a urinary IL-2 positive response during the subsequent BCG course and at week 1 urinary IL-2 was already increased. Comparing the urinary IL-2 kinetics observed during a second or third with a first course, urinary IL-2 tended to be higher during the first and lower during the last weeks. If the interval between subsequent courses was short (12 months or less) significantly higher urinary IL-2 levels at weeks 1 and 2, and a lower level at week 6 were observed. CONCLUSIONS: During a repeat BCG instillation course urinary IL-2 reached a maximum at an earlier week, especially if the interval between the subsequent courses was short. Since an association between urinary IL-2 levels and response to BCG treatment during an induction course has been observed, these immunological data argue in favor of a limited number of instillations during prolonged BCG therapy which could reduce side effects as well as costs.

BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines.

Intravesical bacillus Calmette-Guerin (BCG) is a successful therapy for superficial bladder cancer. However, the working mechanism of BCG after intravesical instillation is not completely understood. A functional role of urothelial (tumor) cells in the initiation of the BCG-induced immune reaction should be considered. Here, the possibility of a causal relationship between BCG-induced interleukin-6 (IL-6) synthesis and BCG internalization by urothelial tumor cells was examined in a series of human transitional bladder cancer (TCC) cell lines with different degrees of differentiation. The results showed that the well differentiated TCC cell lines, RT4, SBC-2, and SBC-7, did not possess the capacity to internalize BCG, which was associated with an inability to upregulate IL-6 synthesis when stimulated with BCG. Moreover, these cell lines expressed a low level of constitutive IL-6 synthesis. In contrast, the poorly differentiated TCC cells, T-24, TCC-SUP and J-82, were able to internalize BCG. In T24 and J82, but not in TCC-SUP cells, BCG internalization appeared to result in an upregulation of IL-6 synthesis. Constitutive IL-6 synthesis of the high grade cell lines was found to be cell line-dependent: both TCC-SUP and J82 cells exhibited a high level of constitutive IL-6 synthesis, whereas T24 cells exhibited a low level. The possible relationship between BCG internalization and IL-6 upregulation was studied in detail with the T24 cell line, which exhibited a low constitutive and high BCG-inducible IL-6 synthesis, using anti-BCG antibodies (alphaBCG) and Cytochalasin B as internalization inhibitors. Upregulation of IL-6 synthesis was significantly inhibited by alphaBCG or Cytochalasin B, indicating that internalization is a prerequisite for BCG-induced upregulation of IL-6 synthesis. In conclusion, upregulation of IL-6 production due to BCG internalization by poorly differentiated bladder carcinoma cells may be part of the mode of action of intravesical BCG therapy.